All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
Diabetes mellitus, hereinafter referred to as diabetes, represents a group of metabolic diseases in which high blood sugar is evident (hyperglycemia), either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger), and if not treated may lead to various complications such as stroke, heart attack, kidney diseases and nerve damage.
Diabetes may be classified as Type 1 or Type 2 diabetes. Type 1 diabetes (juvenile diabetes), also referred to as insulin-dependent diabetes mellitus (IDDM), results from the body's failure to produce insulin. Type 2 diabetes, also referred to as non-insulin-dependent diabetes mellitus (NIDDM), results from insulin-resistance of the cells. Two other forms of diabetes include congenital diabetes, which results from genetic defects of insulin secretion, and gestational diabetes, which occur at about 5% of all pregnant women.
Diabetes without a proper treatment can cause many complications, e.g. hypoglycemia, diabetic ketoacidosis, nonketotic hyperosmolar coma, cardiovascular disease, chronic renal failure, and retinal damage. Adequate treatment of diabetes is thus important, as well as lifestyle factors such as smoking cessation and healthy diet regimen.
Insulin is a peptide hormone composed of 51 amino acids: an A chain of 21 amino acids linked by two disulfide (S—S) bridges to a B chain of 30 amino acids. It is produced in the islets of Langerhans in the pancreas, and is a central player in carbohydrate and fat metabolism regulation in the body. Insulin causes cells to take up glucose from the blood. When insulin is absent, glucose is not taken up by body cells and the body begins to use gluconeogenesis or fat as an energy source. In addition, it has several other anabolic effects throughout the body. Insulin also influences other body functions, such as vascular compliance and cognition. It was also found that enhancing brain insulin signaling by means of intranasal insulin administration also enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the control of whole-body energy homeostasis in humans.
Since the discovery of insulin in 1921, Type 1 diabetes has been treatable by a simple administration of exogenous insulin, most commonly by subcutaneous injections. Type 2 diabetes patients are either insulin resistant, have relatively low insulin production, or both. While Type 2 diabetes has been controlled with medications and diet, certain patients with Type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately. Several surgical attempts to treat diabetes, e.g. pancreas or beta cells transplants (for Type 1 diabetes), and gastric bypass surgery (for Type 2 diabetes), are expensive, complicated and insufficient. Therefore, it is an object of the invention to provide easy, painless and non-invasive administration of insulin for treating diabetes.
Nowadays, insulin cannot be taken orally. This is since when introduced into the gastrointestinal tract, the insulin is subjected to degradation from stomach acid, bile, digestive enzymes and other first pass effects. As a result, the insulin loses all of its activity. Attempts to produce insulin pills for oral administration have yet to succeed. Accordingly, insulin is administered mainly via subcutaneous injections by: a disposable syringe with a needle; an insulin pump; or a repeated-use insulin pen with a needle. Administration schedules attempt to mimic the physiologic secretion of insulin by the pancreas. Hence, both a long-acting insulin and a short-acting insulin are typically used.
Patients who wish to reduce repeated skin puncture of insulin injections often use an injection port in conjunction with syringes, or use insulin pumps. However, both techniques have disadvantages such as cost, the potential for hypoglycemic and hyperglycemic episodes, catheter problems, and no means of controlling insulin delivery based on current blood glucose levels. In addition, indwelling catheters pose the risk of infection and ulceration, and some patients may also develop lipodystrophy due to the infusion sets. In addition, insulin pumps require care and effort to use correctly.
Other administration means have been developed to administer insulin, such as inhalation, transdermal delivery, and intranasal administration, each with its own disadvantages and drawbacks.
Many researches have been conducted to find various methods of therapy for treating diabetes. Nevertheless, the current known methods suffer from one or more inadequacies. Thus, there remains a need for an improved method for administering insulin to treat diabetes. The present invention provides such a contribution to the art based on the finding that insulin can be administered via the oral mucosa by using thin films.
Accordingly, it is an object of the invention to provide a simple, cost efficient and easy to use, advantageous way to administer insulin, without puncturing the patient's skin, by using orally dissolving thin films.
Orally dissolving films, also referred to as mucoadhesive films, eroding thin films or oral bioadhesive films, provide a useful alternative to traditional tablets, capsules, soft gels, liquids and injections. These thin films contain active pharmaceutical ingredient(s), and are designed for intra-oral administration, with the patient placing the strip on or under the tongue (lingual or sublingual) or along the inside of the cheek (buccal). As the thin film dissolves/erodes, drug is released and delivered to the blood stream either intragastrically, buccally or sublingually.
There are two categories of orally dissolving films: fast dissolving films and slow dissolving/eroding ones. Fast dissolving films, usually comprising polymers of high water solubility, are typically designed for lingual administration and gastro-intestinal tract absorption. The active ingredients are incorporated in the film matrix, which rapidly dissolves and is then swallowed for absorption. Fast dissolving films are particularly useful for pediatric and geriatric patients, and for patients with difficulty in swallowing tablets. It is also known in the art to use such films for providing breath freshening agents or various medicaments for treating cold, cough, flu and anti-snoring. These films are generally comprised of a water-soluble polymer(s) suitable for human consumption and compound(s) that enhance the flexibility and wettability of the film, typically selected from polyols, surfactants and other plasticizers.
Slow dissolving films contain at least one slow dissolving or eroding polymer, and are designed for controlled or sustained release of the active agent, primarily for systemic administration via the interior lining of the cheek (buccal mucosa) or for local treatment. U.S. Pat. No. 4,713,243 describes an extruded thin film, useful in intra-oral controlled-releasing delivery.
Thus, it is a further aspect of the invention to provide orally dissolving films containing insulin for immediate- and/or sustained-release of insulin to a patient in need thereof.
Another object of the invention is to provide bioadhesive orally dissolving films containing insulin for improving onset of action, lowering the dosing, and enhancing the efficacy and safety profile thereof. Said films also improve the dosing accuracy relative to other administration forms. Notably, the films of the invention may dissolve rapidly without the need for water, which provides an easy alternative to patients with swallowing disorders and to patients suffering from nausea, such as after chemotherapy.
In yet another aspect of the invention, provided are orally dissolving bilayer films which combine the advantages of both fast- and slow-dissolving films. In another embodiment, the invention provides a single-layer film for immediate- and/or sustained-release of insulin. The films of the invention may further comprise one or more active agents such as tooth whitening materials, breath fresheners, anti-cavity compounds, additional anti-diabetic agents, taste masking agents, flavor agents, etc., which may be delivered to the oral cavity. Both film types provide for ease of application.
An additional aspect of the invention is to provide orally dissolving single-layer films which comprise short-acting forms of insulin (such as lispro, aspart and glulisine) as well as long-acting forms of insulin (such as Neutral Protamine Hagedorn (NPH)/isophane, lente, ultralente, glargine, and detemir), thereby achieving immediate- and prolong-effect.
The films of the invention may comprise additional flavor agents, flavor masking agents, and colorants.
Another aspect of the invention is the method of insulin administration. In certain embodiments, the insulin-containing film is applied to the tongue and adheres to the palate. The film is designed to be flexible and bioadhesive. The film is also designed such that it disintegrates and dissolves upon administration and the drug is released for oral and/or transmucosal absorption. In addition, the films of the invention provide a method to alleviate or eliminate undesired taste or sensation of insulin.
These and other objects and advantages of invention will become apparent as the description proceeds.